Container for preserving blood products at cryogenic temperatures

ABSTRACT

Metallic containers with high toughness characteristics are utilized to cryopreserve blood products and more particularly neonatal stem and progenitor cells at cryogenic temperatures. Metallic containers with high toughness and strength characteristics are durable at low temperatures and are capable to endure high stresses and impacts at −196° C. These containers are better fit to preserve blood products without compromising their sterility or their medical integrity. Methods for fabricating metallic containers are also disclosed.

FIELD OF THE INVENTION

This Invention relates to cryopreservation of blood or blood componentsat cryogenic temperatures.

BACKGROUND OF THE INVENTION

It has been known in blood bank industry that long-term storage of bloodcomponents can be achieved at cryogenic temperature. Plasma can bestored for one year at −18° C. to be thawed and used for therapeuticapplications. Concentrated red blood cells (RBC) treated with glycerolcan be stored for 10 years at −70° C. to be used again. Recently, a newtechnique has been established to cryopreserve hematopoietic stem andprogenitor cells of neonatal or fetal blood. These cells that have beencryopreserved and thawed can be used for autologous reconstitution.Hematopoietic stem cells treated with cryoprotectant fluids are expectedto survive a long-term storage in liquid Nitrogen at −196° C.

Throughout all these cryogenic preservation applications, plasma, RBC,or progenitor stem cells are stored in plastic bags of different shapesand sizes. The reliability of the plastic bag and its viability towithstand the cryogenic environment is very crucial for the sterilityand the integrity of the preserved cells and fluids. It is known thatmaterials become brittle at low temperatures well above that of liquidNitrogen. Embrittled materials have the tendency to crack or fractureunder impact. Thin plastic bags stored at cryogenic temperatures arevery vulnerable to fracture and structural rupture. This conundrum isexasperated as the temperature is lowered and the exposure is prolonged.

Fractured bags render its contents obsolete. This is very costlyespecially when hematopoietic stem and progenitor cells are involved.These cells are cryopreserved for many years to be used for autologousreconstitution. In most cases these cells are lifesavers when needed.Therefore there is a need for a robust and an absolutely reliablecontainer that can safely preserve cells or fluids without compromisingtheir sterility or integrity.

BRIEF DESCRIPTION OF THE INVENTION

The present invention provides a container, which may be used forcollecting and safely storing biological fluids, blood cells, andhematopoietic stem and progenitor cells at temperature ranging fromnormal body temperature to cryogenic liquid Nitrogen temperature. Thecontainer is fabricated of metal that characterized with high strengthand high toughness to endure very low cryogenic temperature and tosuppress any effect of the embrittlement. The container has the shape ofa rectangular parallelepiped with a large flat base and a modest height.All edges are contoured with radius to eliminate high stressconcentration spots on the container structure. The significant aspectratio between the large flat base area and the thin profile of thecontainer enhances the uniformity of phase changing process inside thecontainer. The fine and uniform thickness of the sheet metal coupledwith substantial thermal conductivity greatly improves the consistencyof the freezing process. The container has sealable ports for channelingblood cells or biological fluids.

In a preferred embodiment, the container is fabricated of Austeniticstainless steel sheet metal that characterizes with good toughness atcryogenic temperatures such as 304 and 316 type. This steel alloycontains a high concentration of nickel that greatly enhances itsability to withstand very low temperature environments. Titanium canalso be used to fabricate the container, but the cost could be higher.Titanium has great characteristics in corrosion resistance. Stainlesssteel containers are widely used in automotive, household, food andbeverages, electronics, and medical industries. For example the housingof a wide range of implantable devices such as Pace Makers or DrugDelivery implants are typically made of stainless steel.

There are numerous methods of fabricating metallic containers. All thesemethods are based on processes such as stamping, forming, swaging,drawing, or pressing sheet metals into a specific shapes, then theshapes are joined by crimping, bonding, or welding. For the purpose ofthis invention, it is preferable to fabricate the metallic container bywelding two previously formed half shells. A special tool is used toform the sheet metal in a half shell structure. The half shell havingthe shape of a shallow rectangle with a base referred to herein forwardas planar surface merged by a radius to a surrounding wall referred toherein forward as sidewall. Two symmetrical half shells are matched andwelded at the seam to construct a container. Fluid communication portscould be constructed as an integrated portion of the formed half shells.These integrated portions have the shape of half a cylinder sectioned bya plane along its longitudinal axis. When matching half shells arewelded, these semicircular cylindrical shells form a tubular port at theedge of the container. Many tubular ports could be added to thecontainer using this method.

In another embodiment the metallic tubular ports could be welded to anylocation on the surface of the container after a matching hole is cut onthe surface. Plastic tubing could be bonded to the tubular ports forsterile connection of the container to a blood collection bags set.Additionally, needle ports, or spike ports could be added to tubularports as needed for any aseptic connection to the container.

In a different embodiment the sidewall that surrounds the planar base ona formed half shell, are extended enough to achieve an overlap betweenthe walls of matching half shells. The two half shells are lap weldedand sealed at the overlap between the walls.

In another preferred embodiment, the sidewall that surrounds the planarbase on a formed half shell is terminated with a flat flange of adefined width. The flange circumscribes the wall and is situated in aplane that is parallel to and at a distance from the planar surface. Twosymmetrical half shells are matched and welded at the flange forming asealed container with defined ports. The matching flanges could be laserwelded at the seam or heat resistance weld at the mating surfaces. Thematching flanges could be brazed or bonded at the mating surfaces.

In another preferred embodiment, plastic bushings are sealed bonded orheat welded to the metallic tubular ports to facilitate the bonding ofplastic tubing, spike ports, or needle ports to the container.

In another embodiment, the container internal surface is coated by apolymer such as silicone or laminated by a polymeric liner to addanother protective layer to the container and to broaden the metal alloyselection.

It is common in blood bank industry to separate different blood productsderived from one collected unit of blood. These products are stored indifferent containers and each container is labeled per FDA regulationsand American Society of Blood Banks (AABB) standards. When bloodproducts derived from one donor, are preserved for long-term storage, itis recommended to use more than one storage chamber. This is done inanticipation that a portion of the product can be used in the future andstill keeping another portion in safe storage for potential use. It isalso recommended that these stored portions are maintained in physicallyconnected but safely separable containers. This invention provides a wayof having metallic containers connected by breakable joints. Theseconnected containers used to store blood products can be safelyseparated without compromising the sterility of the stored products, bysimply breaking the joints in between. The invention also provides aholder that securely clinches on two or more containers to maintain themphysically united. These containers can be safely separated by breakingthe holder at specified breakable spots without compromising thesterility of the stored products.

It is preferred in certain applications to have a passageway permittingto channel fluids between the joint containers. These passageways couldbe made of metal or plastic material, and can be sealed or welded. Thecontainers can be safely separated by first sealing each passageway attwo spots and then cut the passageway in between the two sealed spots.The containers are safely separated without compromising the sterilityand the medical integrity of the stored product.

In another embodiment, the container having one enclosure comprising ofmultiple interconnected compartments. Each compartment having at leastone portal for fluid communication and is connected to othercompartments by passageways securing fluid communications between thecompartments. These passageways can be sealed at two spots by weldingmeans, and then are cut in between the welded spots to sterilelyseparate the compartments that are connected by the passageway. Eachseparated compartment can be used by therapeutically processing itscontent or stored again at the cryogenic environment for future use.

In another embodiment, the metallic container is fabricated by weldingthe half shells described above with a flat sheet metal.

In another embodiment, the metallic container encompasses a cone shapededge that merges into a tubular port to facilitate the exiting offluids.

In another embodiment, the metallic container having at least one faceretaining a flexible corrugated geometry. This geometry is flexibleenough to adjust the container shape for limited volume expansion causedby frozen fluids inside the container. Typically metallic containers arestrong enough and tough enough to withstand any level of stress causedby frozen fluid volume expansion. The flexible geometry feature is usedto relief stresses caused by expanding frozen fluid.

Further aspects of the present invention will be apparent from thefollowing description of specific embodiments, the attached drawings andthe appended claims.

BRIEF DESCRIPTION OF DRAWING

The foregoing and other objects, features and advantages of theinvention will be apparent from the following more particulardescription of preferred embodiments of the drawings in which likereference characters refer to the same parts throughout the differentviews. The drawings are not necessarily to scale, emphasis instead beingplaced upon illustrating the principles of the invention.

FIG. 1—Top View of a Container

FIG. 2—Top View of the Internal Section of a Half Shell

FIG. 3—Side View of a welded Container with a Cross SectionDemonstrating Plastic Bushing

FIG. 4—Top View of the Internal Section of a Half Shell with a Flange

FIG. 5—Transversal Cross Section View of a Welded Container with aFlange

FIG. 6—Top View of Joint Containers with Attaching Strip

FIG. 7—Top View of Joint Containers with Fastener and Connected withTubing

FIG. 8—Cross Section View of a Container Fabricated by Welding a HalfShell and a Flat Sheet Metal

FIG. 9—Top View of a Container Having a Cone Shaped Side

FIG. 10—Top View of a Container Having Two Compartments Joined by aPassageway

FIG. 11—Transversal Cross Section View of a welded Container with TowCompartments Joined by a Passageway

DETAILED DESCRIPTION OF THE INVENTION

It is the essence of this invention to provide a durable and toughcontainer that can reliably endure long-term storage at very lowcryogenic temperature environments. Such containers are essential topreserve valuable and perishable contents such as rare blood orprogenitor cells of neonatal. The present invention provides a metalliccontainer characterized with high strength and high toughness to endurevery low cryogenic temperature. It is known that cold temperaturesembrittle materials causing it to fracture at much lower than normalimpacts. By using tough metals that greatly minimize the effect ofembrittlement, containers are capable of withstanding stresses orimpacts at low temperatures.

A top view of a metallic container 20 is shown in FIG. 1. The containeris generally having the shape of a rectangular parallelepiped with alarge flat base and a relatively little height. The large flat base andtop surfaces are referred to as planar surfaces 24. The side surfacethat is substantially perpendicular to and circumscribes the two planarsurfaces is referred to as sidewall 25. The planar surface havingrounded corners 26 enabling the sidewall to blend into a matchingcurvature at each corner. The sidewall also blends with the planarsurfaces along the edges forming a merging contour that minimizes anystress concentration in the structure. FIG. 1 further portrays tubularports 22 used for fluid channeling are extended from the edge of thecontainer. One portal is connected to a plastic tube 42 that could beintegrated with a disposable bags set (not shown) used to collect blood.A second portal is shown having a spike connection port 44. The thirdportal is connected to a needle insertion port 46. Container volume canrange from 1 ml to 1000 ml depending on the application. Tubing 42 couldalso carry at its free end a suitable sterile or aseptic connectiondevice (not shown), to establish communication with a source of materialthat is to be conveyed into the container 20. Once the material istransferred into the container, the tubing 42 can be closed by aconventional radio frequency heat seal, which permits tubing 42 beyondthe seal to be disconnected from the container 20.

In a preferred embodiment, the metallic container is fabricated ofAustenitic stainless steel sheet metal alloy. This steel alloy havinghigh concentration of nickel that greatly enhances its ability towithstand very low temperature environments. As alternative materialTitanium alloy can also be used to fabricate containers. Although thereare many ways of fabricating metallic containers, the most practicalfabrication method for this invention is to weld two previously formedhalf shells. A special tool encompassing the features of the containeris used form a half shell 30 shown in FIG. 2. A large and flat planarsurface 24 is bounded by an undersized sidewall 25. The sidewall blendswith the planar surface in a contoured curvature of a constant radius. Adefined number of extensions 32 having the shape of a half cylindersectioned by a plane passing through its longitudinal axis areoriginated at the top of the sidewall 25. Referring to FIG. 3, a sideview of a welded container is illustrated. Two half shells 30 arematched together and welded at the seam 35. The two half shells arematched in a way that the free end of the sidewall of each half shelltouches the free end of the sidewall of the other half shell. The seam35 is materialized at the contact line between the two sidewalls. It ispreferred to use high precision laser welder technology to join the twohalf shells. Matching extensions 32 of each half shell form acylindrical port 22 at the edge of the container. As shown in the crosssectional are in FIG. 3, it is preferable in some applications to sealbond plastic bushings 48 to the welded tubular ports 22 to facilitatethe bonding of plastic tubing 42, spike ports 44 or needle ports 46 tothe container. The plastic bushings are seal welded or bonded to themetallic tubular ports.

In an alternative embodiment, the sidewalls 25 on the matching halfshells 30 are extended slightly to establish an overlap between thesidewalls used for lap welding.

A top view of a half shell 40 bounded with a flange is shown in FIG. 4.In this configuration, the sidewall 25 that surrounds the planar surface24 is terminated with a flange 34 that is situated in plane parallel tothe planar surface. The flange completely encircles the sidewall andedges all the concaved channels on the extensions 32 along thelongitudinal axis. The flange has a constant width and it is orientedaway from the planar surface and away from the concaved channels on theextensions.

Two symmetrical half shells 40 are matched and welded at the flangeforming a sealed container with defined ports. FIG. 5 shows a crosssectional view of a container fabricated by welding two half shells atthe flange. The matching flanges 34 could be laser welded at the seam35, heat resistance weld, or brazing at the mating flange surfaces 33.The matching flanges could be brazed or bonded at the mating surfaces.

In another method, the container 20 is fabricated by welding two halfshells 30 or 40 that do not have any extension member 32. Tubularcylinders 22 are welded afterward to the container surface after amatching hole is cut allowing for the fluid to channel through thetubular port.

Referring to FIG. 5, a plastic laminate 75 covering the inner wall ofthe enclosure is shown. This laminate is a further step to enhance thebiocompatibility characteristics of the container and allows the usageof different metal alloys such as Aluminum to fabricate the container.In other embodiments a biocompatible coating is used to cover the innersurface of the container to protect the contents.

A top view of rigidly connected containers 20 is shown in FIG. 6. Thesecontainers are attached by one or more welded metallic strip 36. Thesestrips having defined cutting lines 56 that can be easily cut by pliersor scissors. Containers are safely separated by cutting the joiningmetallic strips along the defined cutting lines 56 without compromisingthe sterility of the content in each container.

Alternatively, these containers can be fabricated from previously formedhalf shells that have more than one recessed structure. Such half shellshaving at least two shallow depressions, each embracing a planar basesurrounded by a sidewall, are welded forming two joint containers.

FIG. 7 depicts an alternative way of joining two or more containers. Aholding fastener 38 that securely clinches on two or more containers tomaintain them physically in combination. The fastener having definedbreakable lines 58 strategically placed between the attached containers.Containers can be easily separated by simply breaking the holdingfastener at the breaking line between the containers. The breaking linesecures a safe separation of the containers without compromising thesterility of the contents in each container. FIG. 7 also illustrates aportion of tubing set 50 connected to the joint containers by portals22. This tubing set is originally connected to a set of bags andharnesses (not shown in the figure) to collect blood and separatecomponents. Some bags on the set contain cryoprotectant fluids thatstabilize the cells or membranes for freezing.

Referring to FIG. 8 a cross section view of a container fabricated bywelding a half shell 30 or a flanged half shell 40 to a flat sheet metal45 is shown. FIG. 8 also illustrates a flexible corrugated geometry 70.This geometry is flexible enough to adjust the container shape forlimited volume expansion. The flexible geometry feature is used torelief stresses caused by expanding frozen fluid inside the container.

FIG. 9 demonstrates a top view a container encompassing a coned shapeedge 52 that merges into a tubular port 22 to facilitate the exiting offluids. A little holder 54 attached to the container is used to hold thecontainer to a hook or to an IV pole.

Referring to FIG. 10 and FIG. 11 that demonstrate a container having twocompartments 55 connected by a passageway 60. Each compartment having anidentification label 65 secured to its outer surface. The passageway canbe seal welded at two spots 62 and then is cut across the line 64 tosafely segregate the two compartments. A seal weld 62 assures theintegrity of each compartment and secures the sterility of the content.

Having now described a few embodiments of the invention, it should beapparent to those skilled in the art that the foregoing is merelyillustrative and not limiting, having been presented by way of exampleonly. Numerous modifications and other embodiments are within the scopeof ordinary skill in the art and are contemplated as falling within thescope of the invention as defined by the appended claims and equivalentsthereto. The contents of all references, issued patents, and publishedpatent applications cited throughout this application are herebyincorporated by reference. The appropriate components, processes, andmethods of those patents, applications and other documents may beselected for the present invention and embodiments thereof.

1- Thin wall metallic container to receive biological fluids,comprising; enclosure encompassing a volume confined by a first surfacesituated in a plane, a second surface situated in a plane that isparallel to and at a distance from the first surface, and a sidewallcircumscribing the first and the second surfaces, whereas one edge ofthe sidewall is entirely connected to the periphery of the first surfaceand blends therewith, and the second edge of the sidewall is entirelyconnected to the periphery of the second surface and blends therewith,wherein said enclosure having contoured edges and blended corners, andplurality of portals disposed at the top end of said enclosure, havingmeans to communicate the interior of said enclosure to the exterior,wherein the container is used to cryopreserve blood products atcryogenic temperatures, said blood product including whole blood or anyof its component(s), erythrocytes, leukocytes, platelets, stem cell, andplasma either alone or in combination. 2- The container according toclaim 1, wherein the metallic container is made of stainless steelalloys. 3- The container according to claim 1, wherein the metalliccontainer is made of Titanium alloys. 4- The container according toclaim 1, wherein the metallic container is formed by seal welding twopreviously fabricated and preferably symmetrical half shells, said halfshell having uniform thickness and encompassing a planar basecircumscribed by a sidewall blended by a contoured radius to the planarbase, furthermore said half shells comprise semicircular cylindricalshells extending longitudinally outward from the top edge of thesidewall in a plane parallel to the planar base, said semicircularcylindrical shells form tubular portals when welded to the matchingsemicircular cylindrical shells. 5- The container according to claim 1,wherein the metallic container is fabricated by seal welding a halfshell to an overlay sheet metal, said half shell having uniformthickness and encompassing a planar base circumscribed by a sidewallblended by a contoured radius to the planar base; whereas tubularportals are welded to at least one surface of said container. 6- Thecontainer according to claim 1, wherein plastic bushings are seal bondedor welded to the metallic tubular ports. 7- The container according toclaim 1, wherein at least one face of the container having a curvedsurface arrangement, said arrangement includes concave and convexsurfaces, grooves, and bumps. 8- The container according to claim 1,wherein at least one face of the container having the shape of a funnelconverging to a fluid channeling portal. 9- The container according toclaim 1, wherein at least one face of the container retaining a flexiblegeometric feature having means to relief stresses generated by limitedvolume expansion. 10- The container according to claim 1, wherein themetallic surface is coated with a biocompatible polymer. 11- Thecontainer according to claim 1, wherein a biocompatible plastic laminatecovering the inner surface of said container, wherein the plasticmaterial is selected from a group consisting essentially of silicone,polyvinyl chloride, polyethylene, polypropylene, ethylene-vinyl-acetate,fluropolymers, or copolymers of these materials. 12- The containeraccording to claim 1, wherein a plurality of said container are jointlyinterconnected by breakable metallic bonds with defined breaking linesthat permit each container to separate safely and aseptically when thebond is broken. 13- The container according to claim 1, wherein aplurality of said container are secured to a breakable holder withdefined breaking lines that permit each container to separate safely andaseptically when the holder is broken. 14- Thin wall metallic containerto receive biological fluids, comprising; enclosure having at least twocompartments separated by a partition, each compartment encompassing avolume confined by a first surface situated in a plane, a second surfacesituated in a plane that is parallel to and at a distance from the firstsurface, and a sidewall circumscribing the first and the secondsurfaces, whereas one edge of the sidewall is entirely connected to theperiphery of the first surface and blends therewith, and the second edgeof the sidewall is entirely connected to the periphery of the secondsurface and blends therewith, wherein said compartments having contourededges and blended corners, plurality of portals disposed at the top endof said enclosure with at least one portal per compartment, wherein saidportals having means to communicate the interior of said compartment tothe exterior, and a passageway providing fluid communication betweensaid compartments, wherein said passageway having means to bepermanently sealed preventing any fluid communication there through,wherein the container is used to cryopreserve blood products atcryogenic temperatures, said blood product including whole blood or anyof its component(s), erythrocytes, leukocytes, platelets, stem cell, andplasma either alone or in combination. 15- The container according toclaim 14, wherein the metallic container is made of stainless steelalloys. 16- The container according to claim 14, wherein the metalliccontainer is made of Titanium alloys. 17- The container according toclaim 14, wherein the metallic container is formed by seal welding twopreviously fabricated and preferably symmetrical half shells, said halfshell having at least two depressions, each having uniform thickness andencompassing a planar base circumscribed by a sidewall blended by acontoured radius to the planar base, wherein the matching depressions ofthe welded half shells constitute said compartments, furthermore saidhalf shells comprise semicircular cylindrical shells extendinglongitudinally outward from the top edge of the sidewall in a planeparallel to the planar base, said semicircular cylindrical shells formtubular portals when welded to the matching semicircular cylindricalshells. 18- The container according to claim 14, wherein the metalliccontainer is fabricated by seal welding a half shell having at least twodepressions, each having uniform thickness and encompassing a planarbase circumscribed by a sidewall blended by a contoured radius to theplanar base, to an overlay sheet metal, wherein the depressions and thewelded overlay constitute said compartment, whereas tubular portals arewelded to at least one surface of said compartment. 19- The containeraccording to claim 14, wherein the passageway connecting saidcompartments is completely sealable, whereas compartments joined bypassageway are aseptically separable after sealing connectingpassageway. 20- The container according to claim 14, wherein theenclosure having two compartments constituting one major portion and oneminor portion, each compartment further encompassing at least one portalfor fluid communication and a label on the outer surface of saidcompartment for identification of the contents within.